US10266493B2 - Thioacetate compounds, compositions and methods of use - Google Patents

Thioacetate compounds, compositions and methods of use Download PDF

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US10266493B2
US10266493B2 US13/703,890 US201113703890A US10266493B2 US 10266493 B2 US10266493 B2 US 10266493B2 US 201113703890 A US201113703890 A US 201113703890A US 10266493 B2 US10266493 B2 US 10266493B2
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formula
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US20130202573A1 (en
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Samedy Ouk
Esmir Gunic
Jean-Michel Vernier
Chixu Chen
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Ardea Biociences Inc
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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Definitions

  • Uric acid is the result of the oxidation of xanthine.
  • Disorders of uric acid metabolism include, but are not limited to, polycythemia, myeloid metaplasia, gout, a recurrent gout attack, gouty arthritis, hyperuricaemia, hypertension, a cardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis or sarcoidosis.
  • compositions e.g., for the modulation of serum uric acid levels (sUA) or the treatment of gout or hyperuricemia in individuals in need thereof.
  • compositions comprise and such methods comprise the administration to an individual in need thereof an effective amount of a compound of formula I:
  • a compound of formula (I) wherein one of X 1 , X 2 , X 3 or X 4 is N.
  • Certain specific embodiments provided herein describe a compound of formula (I-A), (I-B), (I-C) or (I-D):
  • a compound of formula (I) wherein two of X 1 , X 2 , X 3 or X 4 are N.
  • Certain specific embodiments provided herein describe a compound of formula (I-E), (I-F) or (I-G):
  • R 3 is H, CH 3 , OCH 3 , CF 3 , F or Cl; and R 4 is H, CH 3 , OCH 3 , CF 3 , F or Cl.
  • R 3 and R 4 are both H.
  • Some embodiments provided herein describe a compound of formula (I), wherein R 3 and R 4 together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring maybe a saturated, an unsaturated or an aromatic ring.
  • n 1, 2, 3 or 4;
  • each R 5 is independently selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF 3 , OH, OCH 3 , ethoxy, SH, SCH 3 , SCH 2 CH 3 , CH 2 OH, C(CH 3 ) 2 OH, Cl, F, CN, COOH, COOR 5′ , CONH 2 , CONHR 5′ or SO 2 NH 2 ; wherein R 5′ is H or C 1-3 alkyl.
  • a compound of formula (I) wherein R a is H or CH 3 ; and R b is H or CH 3 . In specific embodiments, R a and R b are both CH 3 . Certain specific embodiments provided herein describe a compound of formula (I-L):
  • X 1 is CH; X 2 is N; X 3 is CH; and X 4 is CH.
  • R 1 , R 3 and R 4 are all H.
  • R a and R b together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S.
  • R a and R b together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered ring.
  • R a and R b together with the carbon atom to which they are attached form a 3-membered ring.
  • a compound of formula (I), wherein M is H.
  • M is C 1 -C 3 alkyl.
  • M is a pharmaceutically acceptable cation.
  • the pharmaceutically acceptable cation is Na + , Li + , K + , Ca 2+ , Mg 2+ , NH 4 + tetramethylammonium, tetraethylammonium, methylamino, dimethylamino, trimethylamino or triethylamino.
  • Also provided herein in some embodiments is a method of reducing serum uric acid levels in a human, comprising administering to the human an effective amount of a compound of formula (I).
  • Other embodiments provided herein describe a method of treating hyperuricemia in a human with gout, comprising administering to the human an effective amount of a compound of formula (I).
  • Some embodiments provided herein describe a method of treating hyperuricemia in a human, comprising administering to the human an effective amount of a compound of formula (I).
  • Certain embodiments provided herein describe a method of treating gout in a human, comprising administering to the human an effective amount of a compound of formula (I).
  • the condition is gout, a recurrent gout attack, gouty arthritis, hyperuricaemia, hypertension, a cardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or a combination thereof.
  • the condition is gout.
  • any of the methods described further comprise administering a second agent effective for the treatment of the gout.
  • the second agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, or combinations thereof.
  • the second agent is allopurinol, febuxostat, FYX-051, or combinations thereof.
  • substituent groups are specified by their conventional chemical formulas, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left.
  • —CH 2 O— is equivalent to —OCH 2 —.
  • alkyl includes optionally substituted alkyl.
  • the compounds presented herein possess one or more stereocenters. In some embodiments, the stereocenter is in the R configuration, the S configuration, or combinations thereof. In some embodiments, the compounds presented herein possess one or more double bonds. In some embodiments, the compounds presented herein possess one or more double bonds wherein each double bond exists in the E (trans) or Z (cis) configuration, or combinations thereof. Presentation of one particular stereoisomer, regioisomer, diastereomer, enantiomer or epimer should be understood to include all possible stereoisomers, regioisomers, diastereomers, enantiomers or epimers and mixtures thereof.
  • the compounds presented herein include all separate configurational stereoisomeric, regioisomeric, diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • Techniques for inverting or leaving unchanged a particular stereocenter, and those for resolving mixtures of stereoisomers are found, for example, Furniss et al. (eds.), VOGEL′S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; and Heller, Acc. Chem. Res. 1990, 23, 128.
  • moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • reactant refers to a nucleophile or electrophile used to create covalent linkages.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • an optionally substituted group may be un-substituted (e.g., —CH 2 CH 3 ), fully substituted (e.g., —CF 2 CF 3 ), mono-substituted (e.g., —CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., —CH 2 CHF 2 , —CH 2 CF 3 , —CF 2 CH 3 , —CFHCHF 2 , etc).
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons (except in those instances where macromolecular substituents are clearly intended, e.g., polypeptides, polysaccharides, polyethylene glycols, DNA, RNA and the like).
  • “optionally substituted” indicates that the group is optionally substituted with alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, perhaloalkyl, halo, cycloalkyl, cycloalkenyl, heteroalicycl, aryl, heteroaryl, carbocycl, heterocycl, hydroxy, alkoxy, cyano, cyanoalkyl, carboxyl, sulfhydryl, amino, an amino acid, fused cycloalkyl, spiro cycloalkyl, fused heteroaryl, fused aryl, sulfonyl, sulfinyl, sulfonamidyl, sulfamidyl, phoshonate ester, amido, ether, alkylester, or combinations thereof.
  • a group designated as “optionally substituted” indicates that the group is optionally substituted with hydrogen, hydroxy, nitro, cyano, methylthiol, thiol, azido, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-pentyl, iso-pentyl,
  • ethenyl (—CH ⁇ CH 2 ), 1-propenyl (—CH 2 CH ⁇ CH 2 ), isopropenyl [—C(CH 3 ) ⁇ CH 2 ], butenyl, 1,3-butadienyl, ethynyl, 2-propynyl, 2-butyryl, 1,3-butadiynyl, fluoro, chloro, bromo, iodo, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1-chloro-1-fluoro-1-iodoethyl, fluoroethyl, bromoethyl, chloroethyl, iodoethyl, fluoropropyl, bromopropyl, chloropropyl, iodopropyl, fluoroethenyl, chlor
  • C 1 -C x includes C 1 -C 2 , C 1 -C 3 . . . C 1 -C x .
  • C 1 -C 4 indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as the ranges C 1 -C 2 and C 1 -C 3 .
  • C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
  • lower refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about six carbon atoms, more preferably one to three carbon atoms.
  • Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl.
  • hydrocarbon as used herein, alone or in combination, refers to a compound or chemical group containing only carbon and hydrogen atoms.
  • heteroatom or “hetero” as used herein, alone or in combination, refer to an atom other than carbon or hydrogen. Heteroatoms are may be independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
  • alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms.
  • Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • alkylene refers to a diradical derived from the above-defined monoradical, alkyl. Examples include, but are not limited to methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH 2 CH 2 —), isopropylene (—CH(CH 3 )CH 2 —) and the like.
  • alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • the group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (—CH ⁇ CH 2 ), 1-propenyl (—CH 2 CH ⁇ CH 2 ), isopropenyl [—C(CH 3 ) ⁇ CH 2 ], butenyl, 1,3-butadienyl and the like.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2-6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • alkenylene refers to a diradical derived from the above-defined monoradical alkenyl. Examples include, but are not limited to ethenylene (—CH ⁇ CH—), the propenylene isomers (e.g., —CH 2 CH ⁇ CH— and —C(CH 3 ) ⁇ CH—) and the like.
  • alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butyryl, 1,3-butadiynyl and the like.
  • alkynylene refers to a diradical derived from the above-defined monoradical, alkynyl. Examples include, but are not limited to ethynylene (—C ⁇ C—), propargylene (—CH 2 —C ⁇ C—) and the like.
  • aliphatic refers to an optionally substituted, straight-chain or branched-chain, non-cyclic, saturated, partially unsaturated, or fully unsaturated nonaromatic hydrocarbon.
  • the term collectively includes alkyl, alkenyl and alkynyl groups.
  • heteroalkyl refers to optionally substituted alkyl, alkenyl and alkynyl structures respectively, as described above, in which one or more of the skeletal chain carbon atoms (and any associated hydrogen atoms, as appropriate) are each independently replaced with a heteroatom (i.e.
  • an atom other than carbon such as though not limited to oxygen, nitrogen, sulfur, silicon, phosphorous, tin or combinations thereof
  • heteroatomic group such as though not limited to —O—O—, —S—S—, —O—S—, —S—O—, ⁇ N—N ⁇ , —N ⁇ N—, —N ⁇ N—NH—, —P(O) 2 —, —O—P(O) 2 —, —P(O) 2 —O—, —S(O) 2 —, —S(O) 2 —, —SnH 2 — and the like.
  • haloalkyl refers to optionally substituted alkyl, alkenyl and alkynyl groups respectively, as defined above, in which one or more hydrogen atoms is replaced by fluorine, chlorine, bromine or iodine atoms, or combinations thereof.
  • two or more hydrogen atoms may be replaced with halogen atoms that are the same as each another (e.g. difluoromethyl); in other embodiments two or more hydrogen atoms may be replaced with halogen atoms that are not all the same as each other (e.g. 1-chloro-1-fluoro-1-iodoethyl).
  • Non-limiting examples of haloalkyl groups are fluoromethyl and bromoethyl.
  • a non-limiting example of a haloalkenyl group is bromoethenyl.
  • a non-limiting example of a haloalkynyl group is chloroethynyl.
  • perhalo refers to groups in which all of the hydrogen atoms are replaced by fluorines, chlorines, bromines, iodines, or combinations thereof.
  • perhaloalkyl refers to an alkyl group, as defined herein, in which all of the H atoms have been replaced by fluorines, chlorines, bromines or iodines, or combinations thereof.
  • a non-limiting example of a perhaloalkyl group is bromo, chloro, fluoromethyl.
  • a non-limiting example of a perhaloalkenyl group is trichloroethenyl.
  • a non-limiting example of a perhaloalkynyl group is tribromopropynyl.
  • carbon chain refers to any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl group, which is linear, cyclic, or any combination thereof. If the chain is part of a linker and that linker comprises one or more rings as part of the core backbone, for purposes of calculating chain length, the “chain” only includes those carbon atoms that compose the bottom or top of a given ring and not both, and where the top and bottom of the ring(s) are not equivalent in length, the shorter distance shall be used in determining the chain length. If the chain contains heteroatoms as part of the backbone, those atoms are not calculated as part of the carbon chain length.
  • cycle refers to any covalently closed structure, including alicyclic, heterocyclic, aromatic, heteroaromatic and polycyclic fused or non-fused ring systems as described herein. Rings can be optionally substituted. Rings can form part of a fused ring system.
  • membered is meant to denote the number of skeletal atoms that constitute the ring.
  • cyclohexane, pyridine, pyran and pyrimidine are six-membered rings and cyclopentane, pyrrole, tetrahydrofuran and thiophene are five-membered rings.
  • fused refers to cyclic structures in which two or more rings share one or more bonds.
  • cycloalkyl refers to an optionally substituted, saturated, hydrocarbon monoradical ring, containing from three to about fifteen ring carbon atoms or from three to about ten ring carbon atoms, though may include additional, non-ring carbon atoms as substituents (e.g. methylcyclopropyl).
  • a numerical range such as “C 3 -C 6 cycloalkyl” or “C 3-6 cycloalkyl”, means that the cycloalkyl group may consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, i.e., is cyclopropyl, cyclobutyl, cyclopentyl or cycloheptyl, although the present definition also covers the occurrence of the term “cycloalkyl” where no numerical range is designated.
  • the term includes fused, non-fused, bridged and spiro radicals.
  • a fused cycloalkyl may contain from two to four fused rings where the ring of attachment is a cycloalkyl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof. Examples include, but are not limited to cyclopropyl, cyclopentyl, cyclohexyl, decalinyl, and bicyclo[2.2.1]heptyl and adamantyl ring systems. Illustrative examples include, but are not limited to the following moieties:
  • cycloalkenyl refers to an optionally substituted hydrocarbon non-aromatic, monoradical ring, having one or more carbon-carbon double-bonds and from three to about twenty ring carbon atoms, three to about twelve ring carbon atoms, or from three to about ten ring carbon atoms.
  • the term includes fused, non-fused, bridged and spiro radicals.
  • a fused cycloalkenyl may contain from two to four fused rings where the ring of attachment is a cycloalkenyl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • Fused ring systems may be fused across a bond that is a carbon-carbon single bond or a carbon-carbon double bond.
  • cycloalkenyls include, but are not limited to cyclohexenyl, cyclopentadienyl and bicyclo[2.2.1]hept-2-ene ring systems.
  • Illustrative examples include, but are not limited to the following moieties:
  • alicyclyl or “alicyclic” as used herein, alone or in combination, refer to an optionally substituted, saturated, partially unsaturated, or fully unsaturated nonaromatic hydrocarbon ring systems containing from three to about twenty ring carbon atoms, three to about twelve ring carbon atoms, or from three to about ten ring carbon atoms.
  • non-aromatic heterocyclyl and “heteroalicyclyl” as used herein, alone or in combination, refer to optionally substituted, saturated, partially unsaturated, or fully unsaturated nonaromatic ring monoradicals containing from three to about twenty ring atoms, where one or more of the ring atoms are an atom other than carbon, independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but are not limited to these atoms.
  • the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
  • fused, non-fused, bridged and spiro radicals include fused, non-fused, bridged and spiro radicals.
  • a fused non-aromatic heterocyclic radical may contain from two to four fused rings where the attaching ring is a non-aromatic heterocycle, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • Fused ring systems may be fused across a single bond or a double bond, as well as across bonds that are carbon-carbon, carbon-hetero atom or hetero atom-hetero atom.
  • the terms also include radicals having from three to about twelve skeletal ring atoms, as well as those having from three to about ten skeletal ring atoms.
  • Attachment of a non-aromatic heterocyclic subunit to its parent molecule can be via a heteroatom or a carbon atom.
  • additional substitution can be via a heteroatom or a carbon atom.
  • an imidazolidine non-aromatic heterocycle may be attached to a parent molecule via either of its N atoms (imidazolidin-1-yl or imidazolidin-3-yl) or any of its carbon atoms (imidazolidin-2-yl, imidazolidin-4-yl or imidazolidin-5-yl).
  • non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups.
  • Examples include, but are not limited to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2-
  • the terms also include all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • aromatic refers to a planar, cyclic or polycyclic, ring moiety having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer.
  • Aromatic rings can be formed by five, six, seven, eight, nine, or more than nine atoms.
  • Aromatics can be optionally substituted and can be monocyclic or fused-ring polycyclic.
  • aromatic encompasses both all carbon containing rings (e.g., phenyl) and those rings containing one or more heteroatoms (e.g., pyridine).
  • aryl refers to an optionally substituted aromatic hydrocarbon radical of six to about twenty ring carbon atoms, and includes fused and non-fused aryl rings.
  • a fused aryl ring radical contains from two to four fused rings where the ring of attachment is an aryl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • aryl includes fused and non-fused rings containing from six to about twelve ring carbon atoms, as well as those containing from six to about ten ring carbon atoms.
  • a non-limiting example of a single ring aryl group includes phenyl; a fused ring aryl group includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and a non-fused bi-aryl group includes biphenyl.
  • arylene refers to a diradical derived from the above-defined monoradical, aryl. Examples include, but are not limited to 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like.
  • heteroaryl refers to optionally substituted aromatic monoradicals containing from about five to about twenty skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but not limited to these atoms and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
  • heteroaryl includes optionally substituted fused and non-fused heteroaryl radicals having at least one heteroatom.
  • heteroaryl also includes fused and non-fused heteroaryls having from five to about twelve skeletal ring atoms, as well as those having from five to about ten skeletal ring atoms. Bonding to a heteroaryl group can be via a carbon atom or a heteroatom.
  • an imidiazole group may be attached to a parent molecule via any of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol-5-yl), or its nitrogen atoms (imidazol-1-yl or imidazol-3-yl).
  • a heteroaryl group may be further substituted via any or all of its carbon atoms, and/or any or all of its heteroatoms.
  • a fused heteroaryl radical may contain from two to four fused rings where the ring of attachment is a heteroaromatic ring and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • a non-limiting example of a single ring heteroaryl group includes pyridyl; fused ring heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl; and a non-fused bi-heteroaryl group includes bipyridinyl.
  • heteroaryls include, without limitation, furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl, indolizinyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl, purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl,
  • heteroarylene refers to a diradical derived from the above-defined monoradical heteroaryl. Examples include, but are not limited to pyridinyl and pyrimidinyl.
  • heterocyclyl refers collectively to heteroalicyclyl and heteroaryl groups.
  • the number of carbon atoms in a heterocycle is indicated (e.g., C 1 -C 6 heterocycle)
  • at least one non-carbon atom must be present in the ring.
  • Designations such as “C 1 -C 6 heterocycle” refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring.
  • 4-6 membered heterocycle refer to the total number of atoms that are contained in the ring (i.e., a four, five, or six membered ring, in which at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or heteroatoms).
  • those two or more heteroatoms can be the same or different from one another.
  • Heterocycles can be optionally substituted.
  • Non-aromatic heterocyclic groups include groups having only three atoms in the ring, while aromatic heterocyclic groups must have at least five atoms in the ring. Bonding (i.e. attachment to a parent molecule or further substitution) to a heterocycle can be via a heteroatom or a carbon atom.
  • Carbocyclyl refers collectively to alicyclyl and aryl groups; i.e. all carbon, covalently closed ring structures, which may be saturated, partially unsaturated, fully unsaturated or aromatic.
  • Carbocyclic rings can be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms.
  • Carbocycles can be optionally substituted. The term distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon.
  • halogen halo or halide as used herein, alone or in combination refer to fluoro, chloro, bromo and iodo.
  • hydroxy refers to the monoradical —OH.
  • cyano as used herein, alone or in combination, refers to the monoradical —CN.
  • cyanomethyl refers to the monoradical —CH 2 CN.
  • nitro refers to the monoradical —NO 2 .
  • oxy refers to the diradical —O—.
  • oxo refers to the diradical ⁇ O.
  • carbonyl as used herein, alone or in combination, refers to the diradical —C( ⁇ O)—, which may also be written as —C(O)—.
  • alkoxy refers to an alkyl ether radical, —O-alkyl, including the groups —O-aliphatic and —O-carbocyclyl, wherein the alkyl, aliphatic and carbocyclyl groups may be optionally substituted, and wherein the terms alkyl, aliphatic and carbocyclyl are as defined herein.
  • alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • sulfinyl as used herein, alone or in combination, refers to the diradical —S( ⁇ O)—.
  • sulfonyl as used herein, alone or in combination, refers to the diradical —S( ⁇ O) 2 —.
  • sulfonamide refers to the diradical groups —S( ⁇ O) 2 —NH— and —NH—S( ⁇ O) 2 —.
  • sulfamide refers to the diradical group —NH—S( ⁇ O) 2 —NH—.
  • radical arylalkyl is attached to the structure in question by the alkyl group.
  • amino acid refers to a group or compound that consists of an amino group, a carboxyl group, a H atom and a distinctive R group (or side chain).
  • Amino acid includes, ⁇ -amino acids, ⁇ -amino acids, ⁇ -amino acids, and ⁇ -amino acids.
  • ⁇ -Amino acids consists of an amino group, a carboxyl group, a H atom and a distinctive R group which is bonded to the ⁇ -carbon atom.
  • Amino acid includes natural amino acids, unnatural amino acids, amino acid analogs, amino acid mimics, and the like.
  • amino acid refers to one of the naturally occurring twenty amino acids (i.e. ⁇ -amino acids), as shown below.
  • Amino acids consist of an amino group, a carboxyl group, an H atom and a distinctive R group (or side chain), all of which are bonded to an ⁇ -carbon atom.
  • R group or side chain
  • amino acids contain a chiral center, and therefore may exist as either of two optically active enantiomers, the D- and the L-.
  • Naturally occurring acids are found as their L-derivatives.
  • the amino acid is an “unnatural amino acid”, “non-natural amino acid”, “amino acid analog”, “amino acid mimic”. “Unnatural amino acid”, “non-natural amino acid”, “amino acid analog”, “amino acid mimic” and the like, as used herein, refer to an amino acid that is not one of the 20 natural amino acids. These terms refer to amino acids wherein the fundamental amino acid molecule has been modified in some way. Such modifications include, though are not limited to side chain variations; substitutions on, or alterations to, the amino-CH-carboxyl backbone; D-enantiomers; combinations thereof and the like.
  • amino acids which occur naturally but are not naturally incorporated into a growing polypeptide chain such as, though not limited to N-acetylglucosaminyl-L-serine, N-acetylglucosaminyl-L-threonine, O-phosphotyrosine and the like.
  • amino acids which do not occur naturally and may be obtained synthetically or may be obtained by modification of natural, naturally occurring or non-natural amino acids such as, though not limited to N-acetylglucosaminyl-L-serine, N-acetylglucosaminyl-L-threonine, O-phosphotyrosine and the like.
  • amino acids which do not occur naturally and may be obtained synthetically or may be obtained by modification of natural, naturally occurring or non-natural amino acids such as, though not limited to N-acetylglucosaminyl-L-serine, N-acetylglucosaminyl-L-threonine, O-phosphoty
  • side chain variations include though are not limited to, O-t-butyl-serine, hydroxyproline, 4-chlorophenylalanine, homoserine, methionine sulfoxide, thienylalanine and the like.
  • backbone alterations include though are not limited to, ⁇ -amino acids such as ⁇ -alanine, homoproline, alkylation of the amino group, substitution on the ⁇ -carbon atom, thiocarboxyls and the like.
  • a peptide can be natural or unnatural, and consists of amino acids that are linked together.
  • linking groups that can be used as alternatives to the natural peptide bond include, but are not limited to ethylene (—CH 2 —CH 2 —), ethynylene (—CH ⁇ CH—), ketomethylene (—C( ⁇ O)CH 2 — or —CH 2 C( ⁇ O)—), aminomethylene (—CH 2 —NH— or —NH—CH 2 —), methylene ether (—CH 2 —O— or —O—CH 2 —), thioether (—CH 2 —S— or —S—CH 2 —), thioamide (—C( ⁇ S)NH— or —NH—C( ⁇ S)—), ester (—C( ⁇ O)O— or O—C( ⁇ O)—), tetrazole, thiazole and the like.
  • Nucleoside is a glycosylamine consisting of a nucleobase (often referred to simply base) bound to a ribose or deoxyribose sugar.
  • a nucleoside can be a natural nucleoside or an unnatural nucleoside.
  • the term “natural nucleoside” as used herein refers to a nucleobase bound to a ribose or deoxyribose sugar. Examples of these include cytidine, uridine, adenosine, guanosine, thymidine and inosine.
  • nucleoside analog refers to a nucleoside that is not one of the 6 nucleosides. These terms refer to nucleosides wherein the fundamental nucleoside molecule has been modified in some way. Such modifications include, though are not limited to base modifications, sugar modifications, alterations of the linkages between the base and sugar, use of alternate stereochemistries; combinations thereof and the like.
  • nucleotide refers to deoxyribonucleotides, deoxyribonucleosides, ribonucleosides or ribonucleotides and polymers thereof in either single- or double-stranded form, including, but not limited to, (i) analogues of natural nucleotides which have similar binding properties as a reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides; (ii) oligonucleotide analogs including, but are not limited to, PNA (peptidonucleic acid), analogs of DNA used in antisense technology (phosphorothioates, phosphoroamidates, and the like).
  • PNA peptidonucleic acid
  • lipid refers to any fat-soluble (lipophilic), naturally-occurring molecule, such as fats, oils, waxes, cholesterol, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, fatty acid, fatty acid esters, and the like. Lipids can be natural or unnatural.
  • the lipid is a fatty acid.
  • Fatty acids are saturated or unsaturated. Saturated fatty acids include, but are not limited to, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid. Unsaturated fatty acids include, but are not limited to, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid.
  • Phospholipid is a type of lipid that is amphipahtic. Phospholipids are a class of lipids and contain a glycerol backbone, where two of the hydroxy groups of the glycerol backbone are esterified with fatty acid (saturated, unsaturated, natural, unnatural), and the third hydroxy is used to form a phosphate ester with phosphoric acid. The phosphate moiety of the resulting phosphatidic acid is further esterified with ethanolamine, choline or serine. Phospholipids are either natural or unnatural.
  • Natural phospholipids include, but are not limited to, plasmalogen, cardiolipin, dipalmitoylphosphatidylcholine, glycerophospholipid, glycerophosphoric acid, lecithin, lysophosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol (3,4)-bisphosphate, phosphatidylinositol (3,4,5)-trisphosphate, phosphatidylinositol (3,5)-bisphosphate, phosphatidylinositol (4,5)-bisphosphate, phosphatidylinositol 3-phosphate, phosphatidylinositol 4-phosphate, phosphatidylinositol phosphate, phosphatidylmyo-inositol mannosides, phosphatidylserine, platelet-activating factor,
  • glycoside refers to a group comprising any hydrophilic sugar (e.g. sucrose, maltose, glucose, glucuronic acid, and the like).
  • a glycoside is any sugar group bonded through a glycosidic linkage.
  • Glycosides include natural glycosides and unnatural glycosides.
  • Glycosides include asymmetric carbon(s) and exist in L-form or D-form. Natural glycosides preferentially exist in the D-form.
  • Glycosides include monosaccharides, disaccharides, and polysaccharides. Examples of monosaccharides include, but are not limited to, trioses (e.g. glyceraldehyde, dihydroxyacetone), tetroses (e.g.
  • erythrose, threose, erythrulose pentoses (e.g. arabinose, lyxose, ribose, deoxyribose, xylose, ribulose, xylulose), hexoses (allose, altrose, galactose, glucose, gulose, idose, mannose, talose, fructose, psicose, sorbose, tagatose), heptoses (mannoheptulose, sedoheptulose); octoses (e.g. octolose, 2-keto-3-deoxy-manno-octonate), nonoses (e.g.
  • Disaccharide include, but are not limited to, sucrose, lactose, maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose, ⁇ , ⁇ -trehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose, gentiobiulose, mannobiose, melibiose, melibiulose, rutinose, rutinulose, xylobiose.
  • Polysaccharides include glycans. Aza-sugars are also included within the term “glycoside”.
  • polyethylene glycol refers to linear or branched polymeric polyether polyols.
  • the term “patient”, “subject” or “individual” are used interchangeably. As used herein, they refer to individuals suffering from a disorder, and the like, encompasses mammals and non-mammals. None of the terms require that the individual be under the care and/or supervision of a medical professional. Mammals are any member of the Mammalian class, including but not limited to humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like.
  • the individual is a mammal. In preferred embodiments, the individual is a human.
  • treat include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In preferred embodiments, the compounds and compositions described herein are administered orally.
  • an “effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” as used herein, refer to a sufficient amount of at least one agent or compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease.
  • An appropriate “effective” amount may differ from one individual to another.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • prodrug refers to a drug precursor that, following administration to an individual and subsequent absorption, is converted to an active, or a more active species via some process, such as conversion by a metabolic pathway.
  • the term encompasses any derivative of a compound, which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or a pharmaceutically active metabolite or residue thereof.
  • Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to an individual (e.g. by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g. the brain or lymphatic system).
  • a biological compartment e.g. the brain or lymphatic system
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Compounds described herein may possess acidic or basic groups and therefore may react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • composition refers to a biologically active compound, optionally mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, excipients and the like.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
  • pharmaceutical combination refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that at least one of the compounds described herein, and at least one co-agent, are both administered to an individual simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that at least one of the compounds described herein, and at least one co-agent, are administered to an individual as separate entities either simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the individual.
  • cocktail therapies e.g. the administration of three or more active ingredients.
  • co-administration are meant to encompass administration of the selected therapeutic agents to a single individual, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • the compounds described herein will be co-administered with other agents.
  • These terms encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
  • the compounds of the invention and the other agent(s) are administered in a single composition.
  • compounds of the invention and the other agent(s) are admixed in the composition.
  • metabolite refers to a derivative of a compound which is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
  • Described herein are compounds of formula (I), metabolites, pharmaceutically acceptable salts, solvates, polymorphs, esters, tautomers or prodrugs thereof.
  • One embodiment provides a compound of formula (I):
  • X 1 is not C(halogen).
  • provided herein is a compound of formula (I), wherein X 2 and X 4 are both N, and X 1 is N, CH, or C(C1-C4 alkyl). In further or alternative embodiments, provided herein is a compound of formula (I), wherein X 2 is N, X 4 is CH, and X 1 is N, CH, C(halogen) or C(C1-C4 alkyl). In still further or alternative embodiments, provided herein is a compound of formula (I), wherein X 2 is CH, X 4 is N, and X 1 is N, CH, C(halogen) or C(C1-C4 alkyl). In certain embodiments, X 2 and X 4 are both CH, and X 1 is N, CH, C(halogen) or C(C1-C4 alkyl).
  • X 2 and X 4 are both CH, and X 1 is N. In some embodiments, X 2 and X 4 are both CH, and X 1 is CH. In certain embodiments, X 2 and X 4 are both CH, and X 1 is C(halogen). In other embodiments, X 2 and X 4 are both CH, and X 1 is C(C1-C4 alkyl).
  • X 2 is CH, X 4 is N, and X 1 is N. In some embodiments, X 2 is CH, X 4 is N, and X 1 is CH. In certain embodiments, X 2 is CH, X 4 is N, and X 1 is C(halogen). In other embodiments, X 2 is CH, X 4 is N, and X 1 is C(C1-C4 alkyl).
  • X 2 is N, X 4 is CH, and X 1 is N. In some embodiments, X 2 is N, X 4 is CH, and X 1 is CH. In certain embodiments, X 2 is N, X 4 is CH, and X 1 is C(halogen). In other embodiments, X 2 is N, X 4 is CH, and X 1 is C(C1-C4 alkyl).
  • X 2 is N and X 1 is N. In some embodiments, X 2 is N and X 1 is CH. In certain embodiments, X 2 is N and X 1 is C(halogen). In other embodiments, X 2 is N and X 1 is C(C1-C4 alkyl). In further or alternative embodiments, X 2 is CH and X 1 is N. In some embodiments, X 2 is CH and X 1 is CH. In certain embodiments, X 2 is CH and X 1 is C(halogen). In other embodiments, X 2 is CH and X 1 is C(C1-C4 alkyl).
  • X 4 is N and X 1 is N. In some embodiments, X 4 is N and X 1 is CH. In certain embodiments, X 4 is N and X 1 is C(halogen). In other embodiments, X 4 is N and X 1 is C(C1-C4 alkyl). In further or alternative embodiments, X 4 is CH and X 1 is N. In some embodiments, X 4 is CH and X 1 is CH. In certain embodiments, X 4 is CH and X 1 is C(halogen). In other embodiments, X 4 is CH and X 1 is C(C1-C4 alkyl).
  • provided herein is a compound of formula (I), wherein if X 2 and X 4 are both N, then R 4 is not Cl.
  • X 2 is CH
  • X 4 is N
  • R 4 is H, halogen, —CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R 3 and R 4 together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring maybe a saturated, an unsaturated or an aromatic ring.
  • X 2 is N
  • X 4 is CH
  • R 4 is H, halogen, —CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R 3 and R 4 together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring maybe a saturated, an unsaturated or an aromatic ring.
  • X 2 and X 4 are both CH, and R 4 is H, fluoro, chloro, iodo, bromo, —CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R 3 and R 4 together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring maybe a saturated, an unsaturated or an aromatic ring.
  • X 2 is CH
  • X 4 is N
  • R 4 is H, fluoro, chloro, iodo, bromo, —CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R 3 and R 4 together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring maybe a saturated, an unsaturated or an aromatic ring.
  • X 2 is N
  • X 4 is CH
  • R 4 is H, fluoro, chloro, iodo, bromo, —CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R 3 and R 4 together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring maybe a saturated, an unsaturated or an aromatic ring.
  • X 2 and X 4 are both N, and R 4 is fluoro.
  • X 2 and X 4 are both N, and R 4 is iodo.
  • X 2 and X 4 are both N, and R 4 is bromo.
  • X 2 and X 4 are both N, and R 4 is —CN.
  • X 2 and X 4 are both N, and R 4 is C1 to C6 alkyl. In some instances, X 2 and X 4 are both N, and R 4 is C1 to C6 alkoxy.
  • X 2 and X 4 are both N, and R 3 and R 4 together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring maybe a saturated, an unsaturated or an aromatic ring.
  • X 2 and X 4 are both CH, and R 4 is fluoro.
  • X 2 and X 4 are both CH, and R 4 is chloro.
  • X 2 and X 4 are both CH, and R 4 is iodo.
  • X 2 and X 4 are both CH, and R 4 is bromo.
  • X 2 and X 4 are both CH, and R 4 is —CN.
  • X 2 and X 4 are both CH, and R 4 is C1 to C6 alkyl.
  • X 2 and X 4 are both CH, and R 4 is C1 to C6 alkoxy. In other embodiments, X 2 and X 4 are both CH, and R 3 and R 4 together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring maybe a saturated, an unsaturated or an aromatic ring.
  • X 2 is CH, X 4 is N, and R 4 is fluoro.
  • X 2 is CH, X 4 is N, and R 4 is chloro.
  • X 2 is CH, X 4 is N, and R 4 is iodo.
  • X 2 is CH, X 4 is N, and R 4 is bromo.
  • X 2 is CH, X 4 is N, and R 4 is —CN.
  • X 2 is CH, X 4 is N, and R 4 is C1 to C6 alkyl. In some instances, X 2 is CH, X 4 is N, and R 4 is C1 to C6 alkoxy. In other embodiments, X 2 is CH, X 4 is N, and R 3 and R 4 together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring maybe a saturated, an unsaturated or an aromatic ring.
  • X 2 is N, X 4 is CH, and R 4 is fluoro.
  • X 2 is N, X 4 is CH, and R 4 is chloro.
  • X 2 is N, X 4 is CH, and R 4 is iodo.
  • X 2 is N, X 4 is CH, and R 4 is bromo.
  • X 2 is N, X 4 is CH, and R 4 is —CN.
  • X 2 is N, X 4 is CH, and R 4 is C1 to C6 alkyl. In some instances, X 2 is N, X 4 is CH, and R 4 is C1 to C6 alkoxy. In other embodiments, X 2 is N, X 4 is CH, and R 3 and R 4 together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring maybe a saturated, an unsaturated or an aromatic ring.
  • Y 2 is not C—Cl.
  • X 2 is N
  • X 4 is CH
  • Y 2 is N or CR 2
  • R 2 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF 3 , OH, OCH 3 , ethoxy, SH, SCH 3 , SCH 2 CH 3 , CH 2 OH, C(CH 3 ) 2 OH, Cl, F, CN, COOH, COOR 2′ , CONH 2 , CONHR 2′ or SO 2 NH 2 ; wherein R 2′ is H or C 1-3 alkyl.
  • X 2 is CH
  • X 4 is N
  • Y 2 is N or CR 2
  • R 2 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF 3 , OH, OCH 3 , ethoxy, SH, SCH 3 , SCH 2 CH 3 , CH 2 OH, C(CH 3 ) 2 OH, Cl, F, CN, COOH, COOR 2′ , CONH 2 , CONHR 2′ or SO 2 NH 2 ; wherein R 2′ is H or C 1-3 alkyl.
  • X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is H.
  • X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is methyl.
  • X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is ethyl.
  • X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is propyl.
  • X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is isopropyl. In some embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is tert-butyl. In some embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is cyclopropyl. In other embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is cyclobutyl. In some embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is CF 3 .
  • X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is OH. In certain embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is OCH 3 . In some embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is ethoxy. In other embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is SH. In some embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is SCH 3 .
  • X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is SCH 2 CH 3 . In some embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is CH 2 OH. In certain embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is C(CH 3 ) 2 OH. In further or additional embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is F. In some embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is CN.
  • X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is COOH. In certain specific embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is COOR 2′ , wherein R 2′ is H or C 1-3 alkyl. In some embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is CONH 2 . In other embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is CONHR 2′ , wherein R 2′ is H or C 1-3 alkyl. In certain embodiments, X 2 and X 4 are both N, and Y 2 is CR 2 , wherein R 2 is SO 2 NH 2 .
  • X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is H.
  • X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is methyl.
  • X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is ethyl.
  • X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is propyl.
  • X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is isopropyl. In some embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is tert-butyl. In other embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is cyclopropyl. In certain embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is cyclobutyl. In some embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is CF 3 .
  • X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is OH. In some embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is OCH 3 . In some embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is ethoxy. In other embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is SH. In some embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is SCH 3 .
  • X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is SCH 2 CH 3 . In some embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is CH 2 OH. In certain embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is C(CH 3 ) 2 OH. In some instances, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is F. In certain embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is Cl.
  • X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is CN. In other embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is COOH. In some embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is COOR 2′ , wherein R 2′ is H or C 1-3 alkyl. In certain embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is CONH 2 .
  • X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is CONHR 2′ , wherein R 2′ is H or C 1-3 alkyl. In other embodiments, X 2 and X 4 are both CH, and Y 2 is CR 2 , wherein R 2 is SO 2 NH 2 .
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is H.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is methyl.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is ethyl.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is propyl.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is isopropyl. In some embodiments, X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is tert-butyl. In other embodiments, X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is cyclopropyl. In certain embodiments, X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is cyclobutyl.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is CF 3 . In other embodiments, X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is OH. In some embodiments, X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is OCH 3 . In some embodiments, X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is ethoxy. In other embodiments, X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is SH.
  • X 2 is CH, X 4 is N, wherein R 2 is SCH 3 .
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is SCH 2 CH 3 .
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is CH 2 OH.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is C(CH 3 ) 2 OH.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is F.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is Cl.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is CN.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is COOH.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is COOR 2′ , wherein R 2′ is H or C 1-3 alkyl.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is CONH 2 .
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is CONHR 2′ , wherein R 2′ is H or C 1-3 alkyl.
  • X 2 is CH, X 4 is N, and Y 2 is CR 2 , wherein R 2 is SO 2 NH 2 .
  • X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is H.
  • X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is methyl.
  • X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is ethyl.
  • X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is propyl.
  • X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is isopropyl. In some embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is tert-butyl. In other embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is cyclopropyl. In certain embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is cyclobutyl.
  • X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is CF 3 . In other embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is OH. In some embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is OCH 3 . In some embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is ethoxy. In other embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is SH.
  • X 2 is N, X 4 is CH, wherein R 2 is SCH 3 . In certain embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is SCH 2 CH 3 . In some embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is CH 2 OH. In certain embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is C(CH 3 ) 2 OH. In some instances, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is F.
  • X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is Cl. In some embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is CN. In other embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is COOH. In some embodiments, X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is COOR 2′ , wherein R 2′ is H or C 1-3 alkyl.
  • X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is CONH 2 .
  • X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is CONHR 2′ , wherein R 2′ is H or C 1-3 alkyl.
  • X 2 is N, X 4 is CH, and Y 2 is CR 2 , wherein R 2 is SO 2 NH 2 .
  • X 1 and X 2 are both N, then X 3 is not C—Cl.
  • provided herein is a compound of formula (I), wherein X 1 and X 2 are both N, and X 3 is N, CH, C—F, or C(C1-C4 alkyl). In further or alternative embodiments, provided herein is a compound of formula (I), wherein X 1 is N, X 2 is CH, and X 3 is N, CH, C(halogen) or C(C1-C4 alkyl). In still further or alternative embodiments, provided herein is a compound of formula (I), wherein X 1 is CH, X 2 is N, and X 3 is N, CH, C(halogen) or C(C1-C4 alkyl). In certain embodiments, X 1 and X 2 are both CH, and X 3 is N, CH, C(halogen) or C(C1-C4 alkyl).
  • X 1 is CH or N and X 3 is N, CH, C(halogen) or C(C1-C4 alkyl).
  • X 2 is CH or N, and X 3 is N, CH, C(halogen) or C(C1-C4 alkyl).
  • X 1 and X 2 are both CH, and X 3 is N. In some embodiments, X 1 and X 2 are both CH, and X 3 is CH. In certain embodiments, X 1 and X 2 are both CH, and X 3 is C(halogen). In certain embodiments, X 1 and X 2 are both CH, and X 3 is C—F. In certain embodiments, X 1 and X 2 are both CH, and X 3 is C—Cl. In certain embodiments, X 1 and X 2 are both CH, and X 3 is C—Br. In certain embodiments, X 1 and X 2 are both CH, and X 3 is C—I. In other embodiments, X 1 and X 2 are both CH, and X 3 is C(C1-C4 alkyl).
  • X 1 is CH, X 2 is N, and X 3 is N. In some embodiments, X 1 is CH, X 2 is N, and X 3 is CH. In certain embodiments, X 1 is CH, X 2 is N, and X 3 is C(halogen). In certain embodiments, X 1 is CH, X 2 is N, and X 3 is C—F. In certain embodiments, X 1 is CH, X 2 is N, and X 3 is C—Cl. In certain embodiments, X 1 is CH, X 2 is N, and X 3 is C—Br. In certain embodiments, X 1 is CH, X 2 is N, and X 3 is C—I. In other embodiments, X 1 is CH, X 2 is N, and X 3 is C(C1-C4 alkyl).
  • X 1 is N, X 2 is CH, and X 3 is N. In some embodiments, X 1 is N, X 2 is CH, and X 3 is CH. In certain embodiments, X 1 is N, X 2 is CH, and X 3 is C(halogen). In certain embodiments, X 1 is N, X 2 is CH, and X 3 is C—F. In certain embodiments, X 1 is N, X 2 is CH, and X 3 is C—Cl. In certain embodiments, X 1 is N, X 2 is CH, and X 3 is C—Br. In certain embodiments, X 1 is N, X 2 is CH, and X 3 is C—I. In other embodiments, X 1 is N, X 2 is CH, and X 3 is C(C1-C4 alkyl).
  • X 1 is N and X 3 is N. In some embodiments, X 1 is N and X 3 is CH. In certain embodiments, X 1 is N and X 3 is C(halogen). In certain embodiments, X 1 is N and X 3 is C—F. In certain embodiments, X 1 is N and X 3 is C—Cl. In certain embodiments, X 1 is N and X 3 is C—Br. In certain embodiments, X 1 is N and X 3 is C—I. In other embodiments, X 1 is N and X 3 is C(C1-C4 alkyl).
  • X 1 is CH and X 3 is N. In some embodiments, X 1 is CH and X 3 is CH. In certain embodiments, X 1 is CH and X 3 is C(halogen). In certain embodiments, X 1 is CH and X 3 is C—F. In certain embodiments, X 1 is CH and X 3 is C—Cl. In certain embodiments, X 1 is CH and X 3 is C—Br. In certain embodiments, X 1 is CH and X 3 is C—I. In other embodiments, X 1 is CH and X 3 is C(C 1 -C 4 alkyl).
  • X 1 is C(halogen) and X 3 is N. In some embodiments, X 1 is C(halogen) and X 3 is CH. In certain embodiments, X 1 is C(halogen) and X 3 is C(halogen). In certain embodiments, X 1 is C(halogen) and X 3 is C—F. In certain embodiments, X 1 is C(halogen) and X 3 is C—Cl. In certain embodiments, X 1 is C(halogen) and X 3 is C—Br. In certain embodiments, X 1 is C(halogen) and X 3 is C—I. In other embodiments, X 1 is C(halogen) and X 3 is C(C1-C4 alkyl).
  • X 1 is C(C 1 -C 4 alkyl) and X 3 is N. In some embodiments, X 1 is C(C 1 -C 4 alkyl) and X 3 is CH. In certain embodiments, X 1 is C(C 1 -C 4 alkyl) and X 3 is C(halogen). In certain embodiments, X 1 is C(C 1 -C 4 alkyl) and X 3 is C—F. In certain embodiments, X 1 is C(C 1 -C 4 alkyl) and X 3 is C—Cl. In certain embodiments, X 1 is C(C 1 -C 4 alkyl) and X 3 is C—Br.
  • X 1 is C(C 1 -C 4 alkyl) and X 3 is C—I. In other embodiments, X 1 is C(C 1 -C 4 alkyl) and X 3 is C(C 1 -C 4 alkyl).
  • X 2 is CH and X 3 is N. In some embodiments, X 2 is CH and X 3 is CH. In certain embodiments, X 2 is CH and X 3 is C(halogen). In certain embodiments, X 2 is CH and X 3 is C—F. In certain embodiments, X 2 is CH and X 3 is C—Cl. In certain embodiments, X 2 is CH and X 3 is C—Br. In certain embodiments, X 2 is CH and X 3 is C—I. In other embodiments, X 2 is CH and X 3 is C(C 1 -C 4 alkyl).
  • X 2 is N and X 3 is N. In some embodiments, X 2 is N and X 3 is CH. In certain embodiments, X 2 is N and X 3 is C(halogen). In certain embodiments, X 2 is N and X 3 is C—F. In certain embodiments, X 2 is N and X 3 is C—Cl. In certain embodiments, X 2 is N and X 3 is C—Br. In certain embodiments, X 2 is N and X 3 is C—I. In other embodiments, X 2 is N and X 3 is C(C1-C4 alkyl).
  • the compound of formula (I) is not 1-(3-(4-cyanophenyl)pyridin-4-ylthio)cyclopropanecarboxylic acid.
  • Another embodiment provides a compound of formula (I), wherein one of X 1 , X 2 , X 3 or X 4 is N.
  • Another embodiment provides a compound of formula (I) having the structure of formula (I-A), (I-B), (I-C) or (I-D):
  • Another embodiment provides a compound of formula (I) wherein two of X 1 , X 2 , X 3 or X 4 are N.
  • Another embodiment provides a compound of formula (I) having the structure of formula (I-E), (I-F) or (I-G):
  • Another embodiment provides a compound of formula (I) having the structure of formula (I-H), (I-I) or (I-J):
  • Another embodiment provides a compound of formula (I) wherein R 3 is H, CH 3 , OCH 3 , CF 3 , F or Cl; and R 4 is H, CH 3 , OCH 3 , CF 3 , F or Cl.
  • Another embodiment provides a compound of formula (I) wherein R 3 and R 4 are both H.
  • Another embodiment provides a compound of formula (I) wherein R 3 and R 4 together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring maybe a saturated, an unsaturated or an aromatic ring.
  • Another embodiment provides a compound of formula (I) wherein R 3 and R 4 together with the carbon atoms to which they are attached form an optionally substituted, 6-membered aromatic ring.
  • Another embodiment provides a compound of formula (I) having the structure of formula (I-K):
  • Another embodiment provides a compound of formula (I) wherein R a is H or CH 3 ; and R b is H or CH 3 .
  • Another embodiment provides a compound of formula (I) wherein R a and R b are both CH 3 .
  • Another embodiment provides a compound of formula (I) having the structure of formula (I-L):
  • Another embodiment provides a compound of formula (I-L) wherein X 1 is CH; X 2 is N; X 3 is CH; and X 4 is CH.
  • Another embodiment provides a compound of formula (I-L) wherein Y 1 is CR 1 ; and Y 2 is CR 2 .
  • Another embodiment provides a compound of formula (I-L) selected from:
  • Another embodiment provides a compound of formula (I) having the structure of formula (I-M):
  • Another embodiment provides a compound of formula (I-M) wherein R 1 , R 3 and R 4 are all H.
  • Another embodiment provides a compound of formula (I) wherein R a and R b together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S.
  • Another embodiment provides a compound of formula (I) wherein R a and R b together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered ring.
  • Another embodiment provides a compound of formula (I) wherein R a and R b together with the carbon atom to which they are attached form a 3-membered ring.
  • Another embodiment provides a compound of formula (I) wherein M is H.
  • Another embodiment provides a compound of formula (I) wherein M is C1-C3 alkyl.
  • Another embodiment provides a compound of formula (I) wherein M is a pharmaceutically acceptable cation.
  • Another embodiment provides a compound of formula (I) wherein the pharmaceutically acceptable cation is Na + , Li + , K + , Ca 2+ , Mg 2+ , NH 4 + , tetramethylammonium, tetraethylammonium, methylamino, dimethylamino, trimethylamino or triethylamino.
  • the compounds described herein can be prepared by the methods described below.
  • the procedures and examples below are intended to illustrate those methods. Neither the procedures nor the examples should be construed as limiting the invention in any way.
  • compounds described herein are synthesized by any suitable method.
  • the starting materials used for the synthesis of the compounds as described herein are obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis, Mo.). In some embodiments, the starting materials used for the synthesis of the compounds as described herein are synthesized using techniques and materials described, for example, in March, A DVANCED O RGANIC C HEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, A DVANCED O RGANIC C HEMISTRY 4 th Ed., Vols.
  • the compounds described herein can be modified using various electrophiles or nucleophiles to form new functional groups or substituents.
  • the table below entitled “Examples of Covalent Linkages and Precursors Thereof” lists selected examples of covalent linkages and precursor functional groups which yield and can be used as guidance toward the variety of electrophiles and nucleophiles combinations available.
  • Precursor functional groups are shown as electrophilic groups and nucleophilic groups.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Protecting groups are used to block some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means.
  • Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.
  • Protective groups can be removed by acid, base, and hydrogenolysis.
  • Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and, in some embodiments, are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
  • carboxylic acid and hydroxy reactive moieties are also blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc.
  • carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, or they are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups are blocked with fluoride labile silyl carbamates.
  • Allyl blocking groups are useful in then presence of acid- and base-protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid can be deprotected with a Pd-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • the compounds disclosed herein, or intermediate forms thereof are attached to a resin. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
  • protecting or blocking groups are selected from:
  • synthesis of the compounds of the invention are performed following the procedures described below.
  • the thioacetic acid sidechain is attached through nucleophilic substitution reactions and the biaryl bond is constructed by Pd (0) mediated coupling of a boronic acid to an aryl bromide.
  • the resulting biaryl compound can be processed into the desired compounds of formula (I) via standard techniques.
  • Schemes I-A-a thru Scheme I—H-a illustrate some of the synthetic approaches contemplated but are not to be considered limiting in the scope of synthetic methods useful for the preparation of compounds of formula I.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred (e.g., crystalline diastereomeric salts).
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof is prepared by any suitable method.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzo
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedis
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate,
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. WIn some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • Base addition salts can also be prepared by reacting the free acid form of the compounds described herein with a pharmaceutically acceptable inorganic or organic base, including, but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like
  • inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • the salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates.
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the compounds described herein exist as polymorphs.
  • the invention provides for methods of treating diseases by administering such polymorphs.
  • the invention further provides for methods of treating diseases by administering such polymorphs as pharmaceutical compositions.
  • polymorphs include the different crystal packing arrangements of the same elemental composition of a compound.
  • polymorphs have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility.
  • various factors such as the recrystallization solvent, rate of crystallization, and storage temperature cause a single crystal form to dominate.
  • the compounds described herein exist in prodrug form.
  • the invention provides for methods of treating diseases by administering such prodrugs.
  • the invention further provides for methods of treating diseases by administering such prodrugs as pharmaceutical compositions.
  • Prodrugs are generally drug precursors that, following administration to an individual and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. In certain instances, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug a compound as described herein which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • prodrug a short peptide (polyamino acid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • prodrugs are designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues.
  • the design of prodrugs to date has been to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent.
  • prodrug derivatives of compounds described herein can be prepared by methods described herein are otherwise known in the art (for further details see Saulnier et al., Bioorganic and Medicinal Chemistry Letters, 1994, 4, 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound with a suitable carbamylating agent, such as, but not limited to, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • a suitable carbamylating agent such as, but not limited to, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. Indeed, some of the herein-described compounds are prodrugs for another derivative or active compound.
  • prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • prodrugs include compounds wherein a nucleic acid residue, or an oligonucleotide of two or more (e.g., two, three or four) nucleic acid residues is covalently joined to a compound of the present invention.
  • prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters.
  • Compounds having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • free carboxyl groups can be derivatized as amides or alkyl esters.
  • all of these prodrug moieties incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • Hydroxy prodrugs include esters, such as though not limited to, acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sulfonate esters, sulfate esters and disulfide containing esters; ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115.
  • esters such as though not limited to, acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sulfonate esters, sulfate esters and disulfide containing esters;
  • Amine derived prodrugs include, but are not limited to the following groups and combinations of groups:
  • the pharmaceutical compositions comprise an effective amount of a compound of formula I, or a metabolite, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In some embodiments, the pharmaceutical compositions comprise an effective amount of a compound formula I, or a metabolite, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof and at least one pharmaceutically acceptable carrier. In some embodiments the pharmaceutical compositions are for the treatment of disorders. In some embodiments the pharmaceutical compositions are for the treatment of disorders in a mammal. In some embodiments the pharmaceutical compositions are for the treatment of disorders in a human.
  • the compounds and compositions described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
  • Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action.
  • enteral routes including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema
  • parenteral routes injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant, said implant made for example, out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • topical application such as creams or ointments, injection, catheter, or implant, said implant made for example, out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • the administration can also be by direct injection at the site of a diseased tissue or organ.
  • formulations suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient is presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • compositions may be administered topically, that is by non-systemic administration.
  • non-systemic administration includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation.
  • compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compounds or compositions described herein can be delivered in a vesicle, such as a liposome.
  • the compounds and pharmaceutical compositions described herein can also be delivered in a controlled release system, or a controlled release system can be placed in proximity of the therapeutic target.
  • a pump may be used.
  • compositions described herein can also contain the active ingredient in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are optionally prepared according to known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be un-coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as citric acid
  • disintegrants such as starch, alginic acid and certain complex silicates
  • binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols.
  • active compound may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • compositions may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • compositions may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin.
  • the oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion.
  • the injectable solutions or microemulsions may be introduced into an individual's blood-stream by local bolus injection.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • creams, ointments, jellies, solutions or suspensions, etc., containing a compound or composition of the invention can be used.
  • topical application can include mouth washes and gargles.
  • compositions may be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using transdermal skin patches.
  • suitable intranasal vehicles and delivery devices or via transdermal routes, using transdermal skin patches.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof (“active ingredient”) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition may include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • the amount of pharmaceutical composition administered will firstly be dependent on the mammal being treated.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, sex, diet, weight, general health and response of the individual, the severity of the individual's symptoms, the precise indication or condition being treated, the severity of the indication or condition being treated, time of administration, route of administration, the disposition of the composition, rate of excretion, drug combination, and the discretion of the prescribing physician.
  • the route of administration may vary depending on the condition and its severity.
  • the pharmaceutical composition is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. The amount and frequency of administration of the compounds described herein, and if applicable other therapeutic agents and/or therapies, will be regulated according to the judgment of the attending clinician (physician) considering such factors as described above. Thus the amount of pharmaceutical composition to be administered may vary widely.
  • Administration may occur in an amount of between about 0.001 mg/kg of body weight to about 100 mg/kg of body weight per day (administered in single or divided doses), more preferably at least about 0.1 mg/kg of body weight per day.
  • a particular therapeutic dosage can include, e.g., from about 0.01 mg to about 7000 mg of compound, and preferably includes, e.g., from about 0.05 mg to about 2500 mg.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, preferably from about 1 mg to 300 mg, more preferably 10 mg to 200 mg, according to the particular application.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day.
  • the amount administered will vary depending on the particular IC 50 value of the compound used. In combinational applications in which the compound is not the sole therapy, it may be possible to administer lesser amounts of compound and still have therapeutic or prophylactic effect.
  • the compounds described herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof may be administered as a sole therapy.
  • the compounds described herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof may also be administered in combination with another therapy or therapies.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced).
  • the benefit experienced by an individual may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • increased therapeutic benefit may result by also providing the individual with another therapeutic agent for gout.
  • the additional therapy or therapies may include, but are not limited to physiotherapy, psychotherapy, radiation therapy, application of compresses to a diseased area, rest, altered diet, and the like. Regardless of the disease, disorder or condition being treated, the overall benefit experienced by the individual may be additive of the two therapies or therapeutic agents or the individual may experience a synergistic benefit.
  • the compounds described herein need not be administered in the same pharmaceutical composition as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route.
  • the compounds/compositions may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously.
  • the compounds described herein may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol), sequentially or dosed separately to other therapeutic agents.
  • the initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
  • the additional agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, a purine nucleoside phosphorylase (PNP) inhibitor, a uric acid transporter inhibitor, a glucose transporter (GLUT) inhibitor, a GLUT-9 inhibitor, a solute carrier family 2 (facilitated glucose transporter), member 9 (SLC2A9) inhibitor, an organic anion transporter (OAT) inhibitor, an OAT-4 inhibitor, or combinations thereof.
  • PNP purine nucleoside phosphorylase
  • PNP purine nucleoside phosphorylase
  • a uric acid transporter inhibitor a glucose transporter (GLUT) inhibitor, a GLUT-9 inhibitor
  • SLC2A9 solute carrier family 2 (facilitated glucose transporter), member 9 (SLC2A9) inhibitor
  • OAT organic anion transporter
  • OAT-4 inhibitor or combinations thereof.
  • URAT 1 is an ion exchanger that mediates urate transportation.
  • URAT I mediates urate transportation in the proximal tubule.
  • URAT I exchanges urate in a proximal tubule for lactate and nicotinate.
  • xanthine oxidase oxidizes hypoxanthine to xanthine, and further to uric acid.
  • xanthine dehydrogenase catalyzes the conversion of xanthine, NAD + , and H 2 O into urate, NADH, and H + .
  • the additional agent is allopurinol, febuxostat (2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid), FYX-051 (4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile), probenecid, sulfinpyrazone, benzbromarone, acetaminophen, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone (ACTH), colchicine, a glucorticoid, an adrogen, a cox-2 inhibitor, a PPAR agonist, naproxen, sevelamer, sibutmaine, troglitazone, proglitazone, another uric acid lowering agent, losartan, fibric acid, benziodarone, salisylate, anlodipine, vitamin C, or
  • Described herein are methods of treating a disease in an individual suffering from said disease comprising administering to said individual an effective amount of a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • Also described herein are methods of preventing or delaying onset of a disease in an individual at risk for developing said disease comprising administering to said individual an effective amount to prevent or delay onset of said disease, of a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • any disease or disorder in which aberrant levels of uric acid plays a role including, without limitation: hyperuricemia, gout, gouty arthritis, inflammatory arthritis, kidney disease, nephrolithiasis (kidney stones), joint inflammation, deposition of urate crystals in joints, urolithiasis (formation of calculus in the urinary tract), deposition of urate crystals in renal parenchyma, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, gout flare, tophaceous gout, kidney failure, or combinations thereof in a human or other mammal.
  • the methods disclosed herein extend to such a use and to the use of the compounds for the manufacture of a medicament for treating such diseases or disorders. Further, the methods disclosed herein extend to the administration to a human an effective amount of a compound disclosed herein for treating any such disease or disorder.
  • Individuals that can be treated with the compounds described herein, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative of said compounds, according to the methods of this invention include, for example, individuals that have been diagnosed as having gout, gouty arthritis, inflammatory arthritis, kidney disease, nephrolithiasis (kidney stones), joint inflammation, deposition of urate crystals in joints, urolithiasis (formation of calculus in the urinary tract), deposition of urate crystals in renal parenchyma, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, gout flare, tophaceous gout, kidney failure, or combinations thereof.
  • an individual having an aberrant uric acid level is administered an amount of at least one compound disclosed herein sufficient to modulate the aberrant uric acid level (e.g., to a medically-acceptable level).
  • an individual treated with the compounds disclosed herein displays aberrant uric acid levels wherein the uric acid levels in blood exceed a medically-accepted range (i.e., hyperuricemia).
  • an individual treated with the compounds disclosed herein displays aberrant uric acid levels wherein uric acid levels in the blood exceed 360 mmol/L (6 mg/dL) for a female individual or 400 mmol/L (6.8 mg/dL) for a male individual.
  • an individual treated with the compounds disclosed herein displays aberrant uric acid levels wherein uric acid levels in urine exceed a medically-accepted range (i.e., hyperuricosuria). In some embodiments, an individual treated with the compounds disclosed herein displays aberrant uric acid levels wherein uric acid levels in urine exceed 800 mg/day (in a male individual) and greater than 750 mg/day (in a female individual).
  • an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) suffers from a cardiovascular disorder.
  • an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) suffers from an aneurysm; angina; atherosclerosis; a stroke; cerebrovascular disease; congestive heart failure; coronary artery disease; and/or a myocardial infarction.
  • an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) displays (a) c-reactive protein (CRP) levels above about 3.0 mg/L; (b) homocysteine levels above about 15.9 mmol/L; (c) LDL levels above about 160 mg/dL; (d) HDL levels below about 40 mg/dL; and/or (e) serum creatinine levels above about 1.5 mg/dL.
  • CRP c-reactive protein
  • an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) suffers from diabetes. In some embodiments, an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) suffers from Type I diabetes. In some embodiments, an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) suffers from Type II diabetes. In some embodiments, an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) suffers from a loss of beta cells of the islets of Langerhans in the pancreas. In some embodiments, an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) suffers from insulin resistance and/or reduced insulin sensitivity.
  • an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) displays (a) a fasting plasma glucose level ⁇ 126 mg/dL; (b) a plasma glucose level ⁇ 200 mg/dL two hours after a glucose tolerance test; and/or (c) symptoms of hyperglycemia and casual plasma glucose levels ⁇ 200 mg/dL (11.1 mmol/l).
  • an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) suffers from metabolic syndrome.
  • an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) suffers from (a) diabetes mellitus, impaired glucose tolerance, impaired fasting glucose and/or insulin resistance, (b) at least two of (i) blood pressure: ⁇ 140/90 mmHg; (ii) dyslipidaemia:triglycerides (TG): ⁇ 1.695 mmol/L and high-density lipoprotein cholesterol (HDL-C) ⁇ 0.9 mmol/L (male), ⁇ 1.0 mmol/L (female); (iii) central obesity: waist:hip ratio>0.90 (male); >0.85 (female), and/or body mass index>30 kg/m2; and (iv) microalbuminuria:urinary albumin excretion ratio ⁇ 20 mg/min or albumin:creatinine ratio ⁇ 30 mg/g.
  • an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) suffers from insulin resistance (i.e., the top 25% of the fasting insulin values among non-diabetic individuals) and (b) at least two of (i) central obesity: waist circumference ⁇ 94 cm (male), ⁇ 80 cm (female); (ii) dyslipidaemia: TG ⁇ 2.0 mmol/L and/or HDL-C ⁇ 1.0 mmol/L or treated for dyslipidaemia; (iii) hypertension: blood pressure ⁇ 140/90 mmHg or antihypertensive medication; and (iv) fasting plasma glucose ⁇ 6.1 mmol/L.
  • insulin resistance i.e., the top 25% of the fasting insulin values among non-diabetic individuals
  • central obesity waist circumference ⁇ 94 cm (male), ⁇ 80 cm (female)
  • dyslipidaemia TG ⁇ 2.0 mmol/L and/or HDL-C ⁇ 1.0 mmol/L or treated for dyslipidaemia
  • an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) displays at least three of (a) elevated waist circumference: Men ⁇ 40 inches (men) and ⁇ 35 inches (women); (b) elevated triglycerides: ⁇ 150 mg/dL; (c) reduced HDL: ⁇ 40 mg/dL (men) and ⁇ 50 mg/dL (women); (d) elevated blood pressure: ⁇ 130/85 mm Hg or use of medication for hypertension; and (e) elevated fasting glucose: ⁇ 100 mg/dL (5.6 mmol/L) or use of medication for hyperglycemia.
  • an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) suffers from kidney disease or kidney failure.
  • an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) displays oliguria (decreased urine production.
  • an individual treated with the compounds disclosed herein (1) displays aberrant uric acid levels, and (2) produces less than 400 mL per day of urine (adults), produces less than 0.5 mL/kg/h of urine (children), or produces less than 1 mL/kg/h of urine (infants).
  • purines adenine, guanine
  • purines derived from food or tissue turnover (cellular nucleotides undergo continuous turnover)
  • uric acid adenine, guanine
  • guanine is oxidized to xanthine, which is turn is further oxidized to uric acid by the action of xanthine oxidase; adenosine is converted to inosine which is further oxidized to hypoxanthine.
  • xanthine oxidase oxidizes hypoxanthine to xanthine, and further to uric acid.
  • the enzyme hypoxanthine-guanine phosphoribosyltransferase salvages guanine and hypoxanthine.
  • the keto form of uric acid is in equilibrium with the enol form which loses a proton at physiological pH to form urate.
  • uric acid is ionized as the monosodium urate salt.
  • urate is a strong reducing agent and potent antioxidant. In humans, about half the antioxidant capacity of plasma comes from uric acid.
  • uric acid dissolves in blood and passes to the kidneys, where it is excreted by glomerular filtration and tubular secretion. In certain instances, a substantial fraction of uric acid is reabsorbed by the renal tubules.
  • One of the peculiar characteristics of the uric acid transport system is that, although the net activity of tubular function is reabsorption of uric acid, the molecule is both secreted and reabsorbed during its passage through the nephron. In certain instances, reabsorption dominates in the S1 and S3 segments of the proximal tubule and secretion dominates in the S2 segment.
  • the bidirectional transport results in drugs that inhibit uric acid transport decreasing, rather than increasing, the excretion of uric acid, compromising their therapeutic usefulness.
  • normal uric acid levels in human adults (5.1+/ ⁇ 0.93 mg/dL) are close to the limits of urate solubility ( ⁇ 7 mg/dL at 37° C.), which creates a delicate physiologic urate balance.
  • the normal uric acid range for females is approximately 1 mg/dL below the male range.
  • hyperuricemia is characterized by higher than normal blood levels of uric acid, sustained over long periods of time.
  • increased blood urate levels may be due to enhanced uric acid production ( ⁇ 10-20%) and/or reduced renal excretion ( ⁇ 80-90%) of uric acid.
  • causes of hyperuricemia may include:
  • Excessive dietary purine intake foods such as shellfish, fish roe, scallops, peas lentils, beans and red meat, particularly offal—brains, kidneys, tripe, liver
  • foods such as shellfish, fish roe, scallops, peas lentils, beans and red meat, particularly offal—brains, kidneys, tripe, liver
  • Certain medications including low-dose aspirin, diuretics, niacin, cyclosporine, pyrazinamide, ethambutol, some high blood pressure drugs and some cancer chemotherapeutics, immunosuppressive and cytotoxic agents
  • Specific disease states particularly those associated with a high cell turnover rate (such as malignancy, leukemia, lymphoma or psoriasis), and also including high blood pressure, hemoglobin disorders, hemolytic anemia, sickle cell anemia, various nephropathies, myeloproliferative and lymphoproliferative disorders, hyperparathyroidism, renal disease, conditions associated with insulin resistance and diabetes mellitus, and in transplant recipients, and possibly heart disease
  • Abnormal kidney function e.g. increased ATP turn over, reduced glomerular urate filtration
  • hyperuricemia may be asymptomatic, though is associated with the following conditions:
  • gout has increased over the past two decades and, in the United States, affects as much as 2.7% of the population aged 20 years and older, totaling over 5.1 million American adults. Gout is more common in men than women, (3.8% or 3.4 million men vs. 1.6% or 1.7 million women), typically affecting men in their 40's and 50's (although gout attacks can occur after puberty which sees an increase in uric acid levels). An increase in prevalence of gout from 2.9 to 5.2 per 1000 in the time period 1990 to 1999 was observed, with most of the increase occurring in those over the age of 65. Gout attacks are more common in women after menopause. In certain instances, gout is one of the most common forms of arthritis, accounting for approximately 5% of all arthritis cases. In certain instances, kidney failure and urolithiasis occur in 10-18% of individuals with gout and are common sources of morbidity and mortality from the disease.
  • gout is associated with hyperuricemia.
  • individuals suffering from gout excrete approximately 40% less uric acid than nongouty individuals for any given plasma urate concentrations.
  • urate levels increase until the saturation point is reached.
  • precipitation of urate crystals occurs when the saturation point is reached.
  • these hardened, crystallized deposits form in the joints and skin, causing joint inflammation (arthritis).
  • deposits are be made in the joint fluid (synovial fluid) and/or joint lining (synovial lining). Common areas for these deposits are the large toe, feet, ankles and hands (less common areas include the ears and eyes).
  • tissue deposition of urate leads to: acute inflammatory arthritis, chronic arthritis, deposition of urate crystals in renal parenchyma and urolithiasis.
  • the incidence of gouty arthritis increases 5 fold in individuals with serum urate levels of 7 to 8.9 mg/dL and up to 50 fold in individuals with levels>9 mg/dL (530 ⁇ mol/L).
  • gouty nephropathy In certain instances, individuals with gout develop renal insufficiency and end stage renal disease (i.e., “gouty nephropathy”). In certain instances, gouty nephropathy is characterized by a chronic interstitial nephropathy, which is promoted by medullary deposition of monosodium urate.
  • gout includes painful attacks of acute, monarticular, inflammatory arthritis, deposition of urate crystals in joints, deposition of urate crystals in renal parenchyma, urolithiasis (formation of calculus in the urinary tract), and nephrolithiasis (formation of kidney stones).
  • secondary gout occurs in individuals with cancer, particularly leukemia, and those with other blood disorders (e.g. polycythemia, myeloid metaplasia, etc).
  • attacks of gout develop very quickly, frequently the first attack occurring at night.
  • symptoms include sudden, severe joint pain and extreme tenderness in the joint area, joint swelling and shiny red or purple skin around the joint.
  • the attacks are infrequent lasting 5-10 days, with no symptoms between episodes.
  • attacks become more frequent and may last longer, especially if the disorder is not controlled.
  • episodes damage the affected joint(s) resulting in stiffness, swelling, limited motion and/or persistent mild to moderate pain.
  • gout is treated by lowering the production of uric acid. In certain instances, gout is treated by increasing the excretion of uric acid. In certain instances, gout is treated by URAT 1, xanthine oxidase, xanthine dehydrogenase, xanthine oxidoreductase, a purine nucleoside phosphorylase (PNP) inhibitor, a uric acid transporter (URAT) inhibitor, a glucose transporter (GLUT) inhibitor, a GLUT-9 inhibitor, a solute carrier family 2 (facilitated glucose transporter), member 9 (SLC2A9) inhibitor, an organic anion transporter (OAT) inhibitor, an OAT-4 inhibitor, or combinations thereof.
  • URAT 1 xanthine oxidase, xanthine dehydrogenase, xanthine oxidoreductase, a purine nucleoside phosphorylase (PNP) inhibitor, a uric acid transporter (URAT
  • gout treatment In general, the goals of gout treatment are to i) reduce the pain, swelling and duration of an acute attack, and ii) prevent future attacks and joint damage. In certain instances, gout attacks are treated successfully using a combination of treatments. In certain instances, gout is one of the most treatable forms of arthritis.
  • the pain and swelling associated with an acute attack of gout can be addressed with medications such as acetaminophen, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone (ACTH) or colchicine.
  • medications such as acetaminophen, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone (ACTH) or colchicine.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • ACTH adrenocorticotropic hormone
  • colchicine proper medication controls gout within 12 to 24 hours and treatment is stopped after a few days.
  • medication is used in conjunction with rest, increased fluid intake, ice-packs, elevation and/or protection of the affected area/s.
  • the aforementioned treatments do not prevent recurrent attacks and they do not affect the underlying disorders of abnormal uric acid metabolism.
  • reducing serum uric acid levels below the saturation level is the goal for preventing further gout attacks. In some cases, this is achieved by decreasing uric acid production (e.g. allopurinol), or increasing uric acid excretion with uricosuric agents (e.g. probenecid, sulfinpyrazone, benzbromarone).
  • uricosuric agents e.g. probenecid, sulfinpyrazone, benzbromarone
  • allopurinol inhibits uric acid formation, resulting in a reduction in both the serum and urinary uric acid levels and becomes fully effective after 2 to 3 months.
  • allopurinol is a structural analogue of hypoxanthine, (differing only in the transposition of the carbon and nitrogen atoms at positions 7 and 8), which inhibits the action of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine, and xanthine to uric acid. In certain instances, it is metabolized to the corresponding xanthine analogue, alloxanthine (oxypurinol), which is also an inhibitor of xanthine oxidase. In certain instances, alloxanthine, though more potent in inhibiting xanthine oxidase, is less pharmaceutically acceptable due to low oral bioavailability.
  • Allopurinol In certain instances, fatal reactions due to hypersensitivity, bone marrow suppression, hepatitis, and vasculitis have been reported with Allopurinol. In certain instances, the incidence of side effects may total 20% of all individuals treated with the drug. Treatment for disorders of uric acid metabolism has not evolved significantly in the following two decades since the introduction of allopurinol.
  • Uricosuric agents e.g., probenecid, sulfinpyrazone, and benzbromarone
  • probenecid causes an increase in uric acid secretion by the renal tubules and, when used chronically, mobilizes body stores of urate.
  • 25-50% of individuals treated with probenecid fail to achieve reduction of serum uric acid levels ⁇ 6 mg/dL.
  • insensitivity to probenecid results from drug intolerance, concomitant salicylate ingestion, and renal impairment.
  • one-third of the individuals develop intolerance to probenecid.
  • administration of uricosuric agents also results in urinary calculus, gastrointestinal obstruction, jaundice and anemia.
  • saturnine gout a lead-induced hyperuricemia due to lead inhibition of tubular urate transport causing decreased renal excretion of uric acid.
  • more than 50% of individuals suffering from lead nephropathy suffer from gout.
  • acute attacks of saturnine gout occur in the knee more frequently than the big toe.
  • renal disease is more frequent and more severe in saturnine gout than in primary gout.
  • treatment consists of excluding the individual from further exposure to lead, the use of chelating agents to remove lead, and control of acute gouty arthritis and hyperuricaemia.
  • saturnine gout is characterized by less frequent attacks than primary gout.
  • lead-associated gout occurs in pre-menopausal women, an uncommon occurrence in non lead-associated gout.
  • Lesch-Nyhan syndrome affects about one in 100,000 live births.
  • LNS is caused by a genetic deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT).
  • HGPRT hypoxanthine-guanine phosphoribosyltransferase
  • LNS is an X-linked recessive disease.
  • LNS is present at birth in baby boys.
  • the disorder leads to severe gout, poor muscle control, and moderate mental retardation, which appear in the first year of life.
  • the disorder also results in self-mutilating behaviors (e.g., lip and finger biting, head banging) beginning in the second year of life.
  • the disorder also results in gout-like swelling in the joints and severe kidney problems.
  • the disorder leads neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington's disease.
  • the prognosis for individuals with LNS is poor.
  • the life expectancy of an untreated individual with LNS is less than about 5 years.
  • the life expectancy of a treated individual with LNS is greater than about 40 years of age.
  • hyperuricemia is found in individuals with cardiovascular disease (CVD) and/or renal disease.
  • CVD cardiovascular disease
  • hyperuricemia is found in individuals with prehypertension, hypertension, increased proximal sodium reabsorption, microalbuminuria, proteinuria, kidney disease, obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, peripheral, carotid and coronary artery disease, atherosclerosis, congenative heart failure, stroke, tumor lysis syndrome, endothelial dysfunction, oxidative stress, elevated renin levels, elevated endothelin levels, and/or elevated C-reactive protein levels.
  • hyperuricemia is found in individuals with obesity (e.g., central obesity), high blood pressure, hyperlipidemia, and/or impaired fasting glucose. In certain instances, hyperuricemia is found in individuals with metabolic syndrome. In certain instances, gouty arthritis is indicative of an increased risk of acute myocardial infarction.
  • administration of the compounds described herein to an individual are useful for decreasing the likelihood of a clinical event associated with a disease or condition linked to hyperuricemia, including, but not limited to, prehypertension, hypertension, increased proximal sodium reabsorption, microalbuminuria, proteinuria, kidney disease, obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, peripheral, carotid and coronary artery disease, atherosclerosis, congenative heart failure, stroke, tumor lysis syndrome, endothelial dysfunction, oxidative stress, elevated renin levels, elevated endothelin levels, and/or elevated C-reactive protein levels.
  • One embodiment provides a method of treating or preventing a condition characterized by abnormal tissue or organ levels of uric acid in an individual comprising administering to the individual an effective amount of a compound of formula (I).
  • Another embodiment provides the method wherein the condition is gout, a recurrent gout attack, gouty arthritis, hyperuricaemia, hypertension, a cardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or a combination thereof.
  • Another embodiment provides the method wherein the condition is gout.
  • Another embodiment provides the method further comprising administering a second agent effective for the treatment of the gout.
  • the second agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, or combinations thereof.
  • the second agent is allopurinol, febuxostat, FYX-051, or combinations thereof.
  • the compounds described herein are administered to an individual suffering from a disease or condition requiring treatment with a compound that is a diuretic. In some embodiments, the compounds described herein are administered to an individual suffering from a disease or condition requiring treatment with a compound that is a diuretic, wherein the diuretic causes renal retention of urate. In some embodiments, the disease or condition is congestive heart failure or essential hypertension.
  • administration of the compounds described herein to an individual are useful for improving motility or improving quality of life.
  • administration of the compounds described herein to an individual is useful for treating or decreasing the side effects of cancer treatment.
  • administration of the compounds described herein to an individual is useful for decreasing kidney toxicity of cis-platin.
  • kits for the treatment of disorders such as the ones described herein.
  • kits comprise a compound, compounds or compositions described herein in a container and, optionally, instructions teaching the use of the kit according to the various methods and approaches described herein.
  • kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider.
  • Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.
  • Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.
  • the compounds described herein can be utilized for diagnostics and as research reagents.
  • the compounds described herein can be used as tools in differential and/or combinatorial analyses to elucidate expression patterns of genes expressed within cells and tissues.
  • expression patterns within cells or tissues treated with one or more compounds are compared to control cells or tissues not treated with compounds and the patterns produced are analyzed for differential levels of gene expression as they pertain, for example, to disease association, signaling pathway, cellular localization, expression level, size, structure or function of the genes examined.
  • analyses can be performed on stimulated or unstimulated cells and in the presence or absence of other compounds which affect expression patterns.
  • the compounds and formulations of the present invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • Step B Ethyl 2-(3-bromopyridin-4-ylthio)-2-methylpropanoate
  • step A A mixture of 3-bromopyridine-4-thiol (step A, 4.75 g, 25 mmol), ethyl 2-bromoisobutyrate (9.75 g, 50 mmol), and sodium carbonate (7.95 g, 75 mmol) in DMF (50 mL) was stirred at 60° C. for 1 hour.
  • the reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was washed with water (2 ⁇ 100 mL) and saturated sodium chloride (100 mL). The aqueous washes were back extracted with ethyl acetate (2 ⁇ 100 mL).
  • the mixture was loaded on to a 5 g ISCO loading cartridge and eluded with a gradient of 0-100% ethyl acetate in hexane on a 12 g ISCO column to yield ethyl 2-(3-(4-cyanophenyl)pyridin-4-ylthio)-2-methylpropanoate (0.049 g, 70%).
  • step C To ethyl 2-(3-(4-cyanophenyl)pyridin-4-ylthio)-2-methylpropanoate (step C, 49 mg, 0.15 mmol) was added methanol (0.8 mL), and sodium hydroxide (2 M aqueous, 0.8 mL). The resulting mixture was stirred at ambient temperature for 2 hours. The volume was reduced ( ⁇ 0.8 mL) by rotary evaporation. To the residue was added HCl (6 N aqueous) with stirring until pH reached 6, resulting in the formation of a white precipitate, which was isolated by filtration. The solid was washed with water (6 ⁇ 1 mL), air dried for 1 hour and dried under vacuum (P 2 O 5 ) overnight to yield a white powder (28 mg, 64%).
  • the mixture was loaded on to a 5 g ISCO loading cartridge and eluded with a gradient of 0-80% ethyl acetate in hexane on a 40 g ISCO column to yield ethyl 2-(4-(4-cyanophenyl)pyridin-3-ylthio)-2-methylpropanoate as a white powder (1.08 g, 54%).
  • Step B 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile
  • Step D Ethyl 2-(3-bromopyridin-2-ylthio)-2-methylpropanoate
  • Step E Ethyl 2-(3-(4-cyanonaphthalen-1-yl)pyridin-2-ylthio)-2-methylpropanoate
  • Step F 2-(3-(4-cyanonaphthalen-1-yl)pyridin-2-ylthio)-2-methylpropanoic Acid
  • Step A 4-(3-Chloropyrazin-2-yl)-1-naphthonitrile
  • Step B Methyl 2-(3-(4-cyanonaphthalen-1-yl)pyrazin-2-ylthio)acetate
  • Step A methyl 2-(5-bromopyrimidin-4-ylthio)acetate
  • Step B Methyl 2-(4-(4-cyanonaphthalen-1-yl)pyrimidin-5-ylthio)acetate
  • HEK293 human embryonic kidney cells (ATCC# CRL-1573) were propagated in EMEM tissue culture medium as described by ATCC in an atmosphere of 5% CO 2 and 95% air. Transfections of HEK293 cells with a model URAT1 construct was performed using L2000 transfection reagent (Invitrogen) as described by the manufacturer. After 24 h the transfected cells were split into 10 cm tissue culture plates and grown for 1 day after which the medium was replaced with fresh growth medium containing G418 (Gibco) at 0.5 mg/ml final concentration. Drug-resistant colonies were selected after approximately 8 days and then tested for 14 C-uric acid transport activity. The HEK293/URAT1-model cells are plated on Poly-D-Lysine Coated 96-well Plates at a density of 125,000 cells per well.
  • Assay Buffer is 125 mM Sodium Gluconate, 4.8 mM Potassium Gluconate, 1.2 mM Potassium phosphate, monobasic, 1.2 mM magnesium sulfate, 1.3 mM Ca Gluconate, 5.6 mM Glucose, 25 mM HEPES, pH 7.3. Plates were incubated at room temperature for 10 minutes then washed 3 times with 50 ⁇ l Wash Buffer and 3 times with 250 ⁇ l Wash Buffer. Microscint 20 Scintillation Fluid was added and plates were incubated overnight at room temperature to equilibrate. Plates are then read on the TopCount Plate Reader and an EC50 value generated. (See Enomoto et al, Nature, 2002, 417, 447-451 and Anzai et al, J. Biol. Chem., 2004, 279, 45942-45950.)
  • A represents an EC 50 value in the range of ⁇ 10 ⁇ M to >0.5 ⁇ M
  • B represents an EC 50 value in the range of ⁇ 0.5 ⁇ M to >0.05 ⁇ M.
  • C represents an EC 50 value in the range of ⁇ 0.05 ⁇ M to >0.001 ⁇ M.
  • URAT1 EC50 Activity Example Structure Ranking 1A B 2A C 4C B 6B A 2H B 2I A 2J C 2K B 2M A 2N B 2O C 2P C 2Q B 2R A 2S B 2T B 2U B 2V A 2X C 2Y A 2BB B 2CC B 2DD B 2EE B 2FF A 2GG B 2HH A 2II B 2JJ C 2KK B 2LL A 2MM B 2NN C 2PP C 2TT B 2UU C 2VV A 2WW B 2XX B 2YY A 2ZZ B 2AAA C 2BBB B 2CCC B 2DDD B 2EEE B 2FFF C 3A A 4A B 4B A 5A A 6A A 7A A 2B A 2C C 2D B 2E A 2F B 2G A 2L A 2W B 2Z A 2AA B 2OO A 2QQ A 2RR A 2SS A 2GGG B 2HHH A 2III C 2JJJ B

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